SUMMARY A major barrier to HIV cure is the reservoir of latently infected cells that persists in patients treated with highly potent antiretroviral treatment (ART). Activation of these latently infected cells can lead to HIV rebound in the absence of ART. In clinical trials, HIV exhibits widely different dynamics after ART cessation. HIV rebounds rapidly in most individuals, whereas in a small fraction of individuals, prolonged HIV remission or post-treatment control (PTC) is achieved. Despite intensive research, we lack a clear and coherent understanding of the determinants of viral control or the duration of HIV remission after ART, which hinders the development of effective therapeutic strategies to achieve a ?functional? cure and ultimately a sterilizing cure. This grant addresses this gap in knowledge. Our central hypothesis is that PTC is not solely driven by a single factor; rather, it is a phenomenon emerging from complex nonlinear interactions between the immune response and the latent reservoir, including both the replication competent reservoir and the defective reservoir. Understanding this dynamical interaction will be key to develop effective interventions to achieve favorable clinical outcomes. We will first delineate the roles of these interactions in determining viral control through integration of recent biological findings into a mechanistic mathematical model. We will validate this model using clinical data from post-treatment controllers and non-controllers, correlate estimated model parameters with measured biological and immunological markers to identify patient characteristics that predict PTC. Further, we will estimate the mode of action and quantify the efficacy of a next-generation latency reversing agent (LRA), AZD5582, and a class of promising bispecific antibody-based immunotherapeutics, the Dual-Affinity Re-Targeting molecules. Finally, we will integrate models of how these agents work with a model of the interaction of the latent reservoir with the immune system to evaluate and predict the impact of combinations of LRAs and immunotherapeutics on the reservoir and on clinical outcomes. Altogether, our work will provide a theoretical foundation for 1) understanding HIV control and rebound dynamics after ART, 2) identifying patients who are likely to achieve PTC, 3) estimating/predicting the impact of therapeutic interventions such as LRAs and/or immunotherapeutics, and 4) suggesting effective interventions to achieve a ?functional? cure according to patient characteristics.